PPIs exert their pharmacologic effect by inhibiting H-K-ATPase, and enzyme present in the parietal cells of the stomach that is necessary for hydrogen ion transport into the gastric lumen (the final step in gastric acid secretion). Although the currently available PPIs differ in their bioavailability, peak plasma levels, and routes of excreation, it is unknown whether these differences have any clinical significance.

The American Gastroenterological Association (AGA) Institute’s 2008 Technical Review and Medical Position Statement on the Management of Gastroesophageal Reflux Diseasestrongly recommend “antisecretory drugs for the treatment of patients with esophageal gastroesophageal reflux disease (GERD) syndromes (healing esophagitis, symptomatic relief, and maintaining healing of esophagitis). In these uses, PPIs are more effective than histamine-2 receptor antagonists (H2RAs), which are more effective than placebo.” Long-term use of PPIs is recommended for patients with esophagitis once they have proven clinically effective. Also recommended with fair evidence is twice-daily PPI therapy for patients with an esophageal syndrome with an inadequate symptom response to once-daily therapy and once-or twice-daily PPIs for patients with a suspected extra-esophageal GERD syndrome (laryngitis, asthma) with a concomitant esophageal GERD syndrome. This review also concludes that “there is no major difference in efficacy among the currently available PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole).”

PPIs provide the most rapid symptomatic relief and heal esophagitis in the highest percentage of patients with GERD of any of the available medical treatments. The PPIs may be considered therapeutically interchangeable because of their comparable pharmacologic properties, clinical efficacy and safety profiles. Consistent results of clinical trials in patients with duodenal ulcers, gastric ulcers, GERD, hypersecretory conditions, and other acid-related disorders strongly suggest that there is a class effect of PPIs for these disorders, although differences in dosage formulations and drug interactions may occasionally influence choice of PPI in individual cases.

The Oregon Health Resources Subcommittee Report on PPIs states, “By consensus there is no evidence that any PPI has been shown to be superior in comparing outcomes of treatment for gastric ulcer disease, non-steroidal anti-inflammatory drug-induced ulcer, duodenal ulcer, or eradication of Helicobacter pylori.”

The Updated Guidelines for the Diagnosis and Treatment of GERD from the American College of Gastroenterology state: “All of these agents (omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) have been demonstrated to control GERD symptoms and heal esophagitis when used at prescription doses.”

A prospective pharmacoepidemiologic cohort study evaluated the incidence of hospital-acquired pneumonia in patients exposed and unexposed to acid-suppressive medication (n=63,878); hospital-acquired pneumonia occurred in 2219 admissions (3.5%). The unadjusted incidence of hospital-acquired pneumonia was higher in the group exposed to acid suppressive medication than in the unexposed group (4.9% vs 2.0%; odds ratio [OR], 2.6 95% CI, 2.3-2.8). The adjusted OR of hospital-acquired pneumonia in the group exposed to acid suppressive medication was 1.3 (95% CI, 1.1-1.4). A population-based cohort study examined the association between the use of acid suppressive drugs and the occurrence of community acquired pneumonia (CAP; n=364,683). The incidence rates of pneumonia in non-acid suppressive drug users and acid suppressive drug users were 0.6 and 2.45 per 100 person-years, respectively. The adjusted relative risk for pneumonia among persons currently using PPIs compared with those who stopped using PPIs was 1.89 (95% CI, 1.36-2.62).

The interaction of PPIs and clopidogrel is believed to be due to decreased CYP2C19 conversion of clopidogrel to the active metabolite. Omeprazole has been implicated in the interaction due to the moderate inhibition of CYP2C19. Avoid using omeprazole concomitantly or 12 hours apart with clopidogrel. Consider using another acid-reducing agent with less CYP2C19 inhibitory activity. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. For details of clopidogrel-PPI drug interactions, please see Prime Therapeutics Formulary Chapter 13.4A.

In February 2012 the FDA issued a safety warning to healthcare professionals as well as patients that PPIs may be associated with increased risk of C diff associated diarrhea (CDAD).

“FDA has reviewed reports from the FDA's Adverse Event Reporting System (AERS) and the medical literature for cases of CDAD in patients undergoing treatment with PPIs. Many of the adverse event reports involved patients who were elderly, had chronic and/or concomitant underlying medical conditions, or were taking broad spectrum antibiotics that could have predisposed them to developing CDAD. Although these factors could have increased their risk of CDAD, the role of PPI use cannot be definitively ruled out in these reviewed reports.”

The FDA also reviewed 28 observational studies and stated that most studies found the risk of C. diff infection or disease, including CDAD, ranged from 1.4 to 2.75 times higher among patients with PPI exposure compared to those without PPI exposure.

Except for infection, most adverse outcomes associated with PPIs occurred among patients who received long-term therapy. Minimizing the duration of therapy by reviewing periodically a patient’s need for acid-suppressive therapy could reduce the risk of adverse outcomes.

Dosing: All available proton pump inhibitors (PPIs) are available as delayed release products except for omeprazole/sodium bicarbonate (Zegerid). Dosing of PPIs is once daily for most conditions per the prescribing information. More frequent daily dosing may be used in pathologic hypersecretory conditions (Zollinger-Ellison) and Helicobacter pylori (H. pylori) eradication.

Therapeutic Drug Class LimitThe following PPIs are limited to one prescription drug per therapeutic class within a 30 day supply. For example, members may only receive a total of 30 capsules, tablets, or packets per 30 days.

Previous use of samples or vouchers/coupons will not be considered for authorization.

The intent of the PPI generic first program is to encourage the use of cost-effective preferred generic PPIs prior to the use of brand PPIsand high cost generic PPIs. Brand name and generic (Nexium/esomeprazole & Dexilant) PPIs will be paid at the same amount as generic omeprazole, if any one of the following is met:

The patient’s medication history includes use of a generic PPI OR

The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity, to the generic PPI prerequisites.

Generic Zegerid will be covered if the following is met:

The patient has failed all generic and OTC PPI medications OR

The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity, to the generic and OTC PPI prerequisites.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

10/27/2015: Policy section updated to state: Previous use of samples or vouchers/coupons will not be considered for authorization.

04/01/2016: Policy description updated to add generics rabeprazole and esomeprazole to the table regarding Maximum Daily Dosage. First policy statement revised to state that the intent of the PPI generic first program is to encourage the use of cost-effective preferred generic PPIs prior to the use of brand PPIs and high cost generic PPIs. Added generic esomeprazole to the first policy statement. Added policy statement that generic Zegerid will be covered if certain criteria are met. Investigative definition updated in policy guidelines section.